The present invention is related to the prolonged release of an active agent from a dosage form. More particularly, it relates to a an active agent dosage form adapted for retention in the stomach for a sustained period for delivering the active agent to a fluid environment of use.
Controlled release dosage forms that provide for prolonged delivery of active agent formulations to the environment of use have found application for increasing numbers of active agents. However, with respect to pharmaceutical and veterinary active agent formulations, there has been a need not only to provide for prolonged delivery of the active agent over time, but also to provide prolonged delivery of the active agent at a particular location or locations in the environment of use, such as in the stomach.
Certain active agents are absorbed primarily from the small intestine. Generally, the time of passage of different particles through the small intestine does not vary significantly, and passage is generally independent of food intake and particle size. Thus, active agent dissolved in liquid, solid active agent dispersed in liquid and relatively larger delivery units of active agent, such as microcapsules and the like, will traverse the length of the small intestine in substantially the same time frame, usually about 3-5 hours. For active agents that are not easily absorbed by the small intestine or that do not dissolve readily, the window for active agent absorption in the small intestine may be too short to provide a desired therapeutic effect. This fact often creates a need for frequent dosing of active agent in order to provide and maintain adequate levels of active agent in blood plasma. The need for frequent dosing presents compliance problems and is often inconvenient for the user as well.
Since it has been found difficult to alter the transit time of active agent through the small intestine, some emphasis has been placed on attempting to control the transit time of active agents in the stomach. Most active agents are not well absorbed in the stomach, but even in those instances where the active agent is not well absorbed, the continuous release of active agent in the stomach over a prolonged time period will dispense active agent over that same period of time to the small intestine where it can be absorbed. While there is a sound basis for such an approach, physiological characteristics of the stomach and the digestive process have not allowed for much prior success, since the residence time of a particle in the stomach is only mildly dependent of food intake or particle size.
The physiological behavior of the stomach is usually determined by whether it contains food or is empty. Food is mixed and partially digested in the distal stomach (antrum). As the stomach undergoes contractions, partially digested material is discharged into the small intestine and non-digested material is retropelled into the main part of the stomach for further digestion. In the fed state, non-digestible material is not generally able to leave the stomach. At the end of a digestive period, the stomach enters the fasting stage and begins a cycle called the interdigestive myoelectric motor cycle or IMMC.
The IMMC can be considered to be divided into four phases: (1) phase 1 is an approximately one hour period with no contractions; (2) phase 2 is about a forty minute period of intermittent potentials and contractions that increase in intensity over time; (3) phase 3 is a relatively short period, generally between about five to fifteen minutes, of intense contractions (commonly called the xe2x80x9chousekeeper wavexe2x80x9d) that completely empties the stomach; and (4) phase 4 is a short transitory period between the intense activity of phase 3 and the quiescence of phase 1. The different phases move distally from the stomach to the terminal ileum over an approximately two hour period as the cycle is repeated. Since the cycle is interrupted by the receipt of food by the stomach, it is possible to delay the emptying phase, phase 3, by maintaining a fed state. However, it is not practical to regularly maintain the fed state over a long period of time. Consequently, a need exists for a delivery device that can remain in the stomach for a significant period, whether in the fed or fasted state, and deliver active agent to the stomach over a prolonged period of time.
A variety of studies have been conducted in dog and in man to determine sizes of objects that would be retained in the stomach during the fed stage and also in the fasting stage when IMMC is present. Khosla and Davis, International Journal of Pharmaceutics, Vol. 62 (1990), pages R9-R11 have reported that a particle size less that 2 mm generally results in emptying from the stomach of the dog. Non-disintegrating tablets having sizes of 7, 11 and 13 mm in diameter were emptied from the human stomach, but the larger sized tablets tended to remain in the stomach longer than the small sized tablets. Tablets larger than 11 mm tended to be emptied only during the IMMC. Davis et al., Pharmaceutical Research, Vol. 8, No. 10 (1991) has described retention of radio-telemetry capsules having a size of 25xc3x978 mm in the stomach of human subjects past phase 3 of the IMMC. Timmermans et al., Journal of Pharmaceutical Sciences, Vol. 82, No. 8 (1993) has reported the mean resting pyloric diameter in humans as 12.8xc2x17.0 mm. Accordingly, it is important that gastric retentive delivery vehicles are adapted to disintegrate, dissolve or erode to sizes that permit eventual elimination of the vehicle without causing gastric obstruction.
Various attempts to provide active agent delivery devices that remain in the stomach for extended periods or time have been described previously. For example, U.S. Pat. No. 4,851,232 describes a hydrogel reservoir containing tiny pills having a active agent core surrounded by a wall controlling delivery of active agent to the stomach. The hydrogel swells in the stomach to facilitate retention of the active agent reservoir in the stomach over time.
U.S. Pat. No. 4,871,548 describes a dosage form including a mixture of low and high number average molecular weight hydroxypropylmethylcellulose polymers and active agent that swells when in the stomach.
U.S. Pat. No. 4,767,627 describes substantially planar devices formed of bioerodible polymer including active agent that may be compressed and folded for oral administration and then released and unfolded in the stomach, where the devices are to be retained over an extended period of time. The devices have a longest diameter of between 1.6 and 5 cm. It is suggested that as an alternative to incorporating the active agent into the device a controlled release active agent module, mechanically or osmotically driven, can be glued or tethered to the device.
U.S. Pat. No. 5,443,843 describes a plurality of compressible retention arms and an attached controlled release device which in the expanded form resists gastrointestinal transit. The system can have a collar or a belt for receiving and holding a active agent-containing, orally-administrable controlled release device. In a fully expanded configuration for human use, the system is described as having minimum and maximum dimensions of 2.5 and 6.0 centimeters, respectively.
U.S. Pat. No. 5,007,790 describes a sustained release active agent dosage form in the form of a capsule or tablet that includes a plurality of hydrophilic water-swellable, cross-linked polymer particles that swell in the stomach to promote gastric retention and permit gastric fluid to penetrate the particles to dissolve active agent and deliver it to the stomach in the solution state. The particles are indicated to retain their physical integrity over the dosing period. Initially sized particles, indicated to be preferably spherical, are disclosed to be in the range of 50 xcexcm to 2 mm, swell to a size of about 3 mm. A plurality of particles are packed into a capsule for administration to a patient.
U.S. Pat. No. 5,582,837 describes a dosage form similar to that of U.S. Pat. No. 5,007,790, without the use of a cross-linked hydrophilic polymer. The particles are described as slippery and soft, preferably spherical, and having dimensions on the order of 6 to 18 mm in the swollen state. The particles can be packed into capsules containing 7-25 spherical particles, depending on the size, or formulated into tablets that contain from 2-25 spherical particles.
The use of albumin-cross-linked polyvinylpyrrolidone hydrogels to deliver flavin mononucleotide to dogs has been described by Park et al. in Journal of Controlled Release, Vol.19 (1992) pages 131-134. The hydrogels were maintained in the stomachs of dogs for extended periods, even in the fasted state. Gels with a glassy core tended to remain in the stomach longer than hydrogels without the glassy core. Control of the size of the core was attempted by administration of water in the stomach. While it is possible to control the dimensions of the hydrogel in the dry state, controlling the size of the glassy core within the hydrogel after administration to a subject by addition of water is not suitable for fabrication of a dosage form that can routinely and controllably be retained in the stomach of a subject over a prolonged period of time.
While it is important that the delivery device be adapted to remain in the stomach for a prolonged period, it is also important that the device deliver active agent in a controlled manner. Delivery systems, such as those described below, are representative of the many different systems have been suggested for such controlled delivery of active agents over a prolonged period of time.
For example, U.S. Pat. No. 4,290,426 to Lusted et al describes a cylindrical dispenser for releasing a beneficial agent into a fluid environment at a rate that is governed by the fluid induced relaxation of a polymeric agent contained within the dispenser. The cylindrical dispenser includes an impermeable container that has within it a reservoir and a passageway from the reservoir to the exterior of the container. The reservoir contains a polymer and a beneficial agent. The polymer imbibes fluid from the environment and thereby undergoes relaxation, releasing the beneficial agent from the device. The amount of agent released is dependent on the rate of relaxation of the polymer over time.
Coated dosage forms have also been suggested for delivery of a controlled amount of a beneficial agent over a prolonged period of time. U.S. Pat. No. 5,256,440 describes a process for producing a film coated dosage form. A continuous groove is inscribed in a dosage form core. A latex film is coated onto the core, the groove defining a fixed zone and a detachable zone for the film. The detachable portion of the latex film detaches when it is exposed to the environment of use, thereby exposing a discrete portion of the dosage form core surface. The remainder of the film remains attached to the dosage form core. The exposed portion of the dosage form surface erodes and releases active agent to the environment of use.
Coated tablets for constant and prolonged active agent release are described by Conte et al in J. Controlled Release, Vol. 26, (1993) pages 39-47. These GEOMATRIX(trademark) Systems are swellable matrices that are coated or tableted with polymeric barrier layers. Release performances of the systems are modulated as a result of the reduction of the releasing surface exposed to the dissolution medium by the polymeric barrier layer coatings. As the extent of coating of the system""s surface is increased, the release kinetics of the system shift toward constant release. These systems are further described in U.S. Pat. No. 4,839,177 to Colombo et al.
U.S. Pat. No. 5,534,263, which is incorporated herein by reference, describes a dosage form useful for the prolonged delivery of an active agent formulation in the form of a matrix having two or more insoluble bands on the surface of the matrix. The exposed surfaces of the matrix erode in a manner that creates additional surface areas to provide for prolonged release of an active agent formulation with determined release profiles.
Additional oral, controlled-release dosage forms include elementary osmotic pumps, such as those described in U.S. Pat. No. 3,845,770, mini-osmotic pumps such as those described in U.S. Pat. Nos. 3,995,631, 4,034,756 and 4,111,202, and multi-chamber osmotic systems referred to as push-pull, push-melt and push-stick osmotic pumps, such as those described in U.S. Pat. Nos. 4,320,759, 4,327,725, 4,449,983, 4,765,989 and 4,940,465, all of which are incorporated herein by reference.
Administration of acyclovir by sipped solution over a four-hour period has been described in Br. J. clin. Pharmac., 21, 459-462 (1986) to achieve an increased contact time with the human stomach and the gastrointestinal tract. The total amount of acyclovir absorbed was increased over that observed with administration of acyclovir tablets. The influence of food on gastric retention time and the absorption of acyclovir has been reported in International Journal of Pharmaceutics, Vol. 38 (1987), pages 221-225. As reported there, compared to a lighter meal, the heavier meal slowed the rate of gastric emptying, prolonged small intestinal transit time and decreased absorption of the active agent.
As can be observed in the above-referenced patents and publications, devices have been described that provide for prolonged delivery of an active agent and retention in the gastric environment. However, there remains a continuing need for improved systems for delivering an active agent to the gastric environment over a prolonged period of time and in a reliable, controllable and reproducible manner. In particular, there is a need for sustained delivery devices that are to remain in the stomach, even during a fasting state in which IMMC is present, for a prolonged period, for example from about 4 hours to up to about 20-24 hours. Such devices should exhibit a combination of flexibility and rigidity so as not to be expelled from the stomach into the pyloric sphincter under fed or fasting conditions, and deliver active agent in a reproducible, controlled manner, over a prolonged period of time.
Accordingly, the present invention is directed to a dispensing device that will provide increased retention time of the device in the stomach over conventional dosage forms and release an active agent formulation in a reliably controllable manner, and further that is easy and inexpensive to manufacture.
In one aspect, the invention is directed to an active agent dosage form for the prolonged delivery of an active agent to the stomach of a human or other animal. The dosage form includes an active agent and a polymer matrix formed of a mixture of a swellable, water soluble polymer that expands when in contact with fluids in the gastric environment and a hydroattractant, preferably water insoluble. The matrix is formed with a rigid or semi-rigid segment in which swelling of the hydrogel is constrained to provide a rigid or semi-rigid section in the dosage form that facilitates the dosage form remaining in the stomach of a subject over a prolonged period of time. In one embodiment, the rigid or semi-rigid section of the dosage form comprises one or more insoluble materials, typically exhibiting low water impermeability and formed as a band circumscribing a portion of the surface of the matrix, that along with the banded portion of the polymer matrix forms the rigid or semi-rigid segment of the dosage form.
The aforementioned insoluble material or band (or bands, if more than one band is utilized) prolongs the period of time in which the polymer matrix retains its integrity in an expanded state and increases the residence time of the dosage form in the stomach. The band limits the transport of fluid into the portion of the polymer matrix which it surrounds and provides the polymer matrix with enough rigidity to permit the dosage form to resist the compressive force of the contractions of the stomach during the housekeeping phase and remain in the stomach for a significantly prolonged period. As the dosage form erodes in the stomach or as active agent diffuses from the matrix, active agent will be released and either absorbed by the stomach or passed from the stomach to the small intestine where it can be absorbed.
In still another aspect, the active agent dosage form comprises (a) a therapeutically-effective amount of an active agent, (b) a polymer matrix in which the active agent is dissolved or dispersed, the polymer matrix including a high molecular weight, water-soluble polymer and a hydroattractant such as a water-insoluble polymer, and, optionally, non-polymeric water-soluble excipients and polymers of molecular weight of less than 10,000 grams per mole, the polymer matrix having an outer surface for exposure to the environment of use, and (c) a band of insoluble material circumscribing a portion of the outer surface of the polymer matrix.
Examples of water soluble polymers are sodium and calcium polyacrylic acid, polyacrylic acid, polymethacrylic acid, polymethylvinylether co-maleic anhydride, polyvinylpyrrolidone, polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxymethyl methacrylate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, methyl cellulose, maltodextrin, xanthan gum, tragacanth gum, agar, gellan gum, kayara gum, alginic acids, pectins, pre-gelatinized starch, and polyvinyl alcohol, and blends of those polymers. Particularly useful polymer blends are those which form association polymers in the low pH environment of the stomach, such as mixtures of polyacrylic acid and polyethylene oxide or mixtures of polyacrylic acid and polyvinylpyrrolidone.
Examples of hydroattractants are water insoluble polymers such as low substituted hydroxypropyl cellulose, ion exchange resins, microcrystalline cellulose, cross-linked sodium or calcium carboxymethyl cellulose, cellulose fiber, cross-linked polyvinyl pyrrolidone, cross-linked polyacrylic acid, cross-linked Amberlite resin, alginates, chitin, colloidal magnesium-aluminum silicate, corn starch granules, wheat starch granules, rice starch granules, potato starch granules, zein, soya polysaccharide, and sodium carboxymethyl starch, and blends of these hydroattractants.
Examples of non-polymeric water soluble excipients include sugars, such as mannitol, sorbitol, sucrose, lactose, fructose, maltose; salts such as sodium chloride, potassium chloride, calcium sulfate; the ammino acids alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tryosine, and valine; buffering agents such as citric acid, sodium citrate, potassium citrate, succinic acid, fumaric acid, sodium acetate, sodium phosphate monobasic, tartaric acid, sodium potassium tartrate; surface active agents such as poloxamers, polysorbates, lecithin and the like; and effervescing couples such as citric acid blended with sodium bicarbonate, and similar blends. Malodextrin, having a molecular weight of about 400 to 4000 grams per mole, and polymers having similar properties are example of a low molecular weight polymeric materials useful in this invention.
In another aspect, the invention comprises an active agent dosage form adapted to deliver in the stomach, as a single dose and over a prolonged time period, a therapeutically effective amount of the active agent with the relative absorption index of the active agent over the time period being at least 0.5. Preferably, the amount of active agent delivered over the prolonged period by the present invention will be at least 50%, and most preferably at least 80%, of the amount of active agent deliverable in an immediate release, multiple dose regimen over the time period.
In still another aspect, the invention comprises an active agent dosage form adapted for gastric retention over a prolonged period comprising a polymer matrix formed of a water soluble, high molecular weight polymer and a hydroattractant in which the weight percent of the water soluble, high molecular weight polymer is about 10 to 50 weight percent and the weight percent of the hydroattractant is about 5 to 70 weight percent.
In a further aspect of the invention, the invention comprises a composition comprising about 5 weight percent to about 50 weight percent of a polyethylene oxide polymer having a number average molecular weight of between about 100,000 and 9 million grams per mole and about 5 weight percent to about 70 weight percent of a hydroxypropyl cellulose polymer having a hydroxypropyl content of between about 10 weight percent to about 13 weight percent of the hydroxypropyl cellulose polymer.
In another aspect of the invention, the dosage form is formed as a swellable polymer matrix attached to a separate active agent reservoir, from which the active agent is delivered, such as an osmotically-driven active agent reservoir. The polymer matrix is formed as a tube or annular ring and placed about the reservoir, such that swelling of the polymer retains the active agent reservoir within the tube or ring and provides size and gel properties to the dosage form that promotes retention in the stomach over a prolonged period of time. The polymer tube or annular ring is optionally formed with split ends such that upon swelling the ends of the polymer matrix can flare away from the reservoir to substantially increase the effective swollen size of the dosage form over that exhibited in the dry state. The active agent reservoir contributes to the rigidity of the dosage form, such that along with the gel properties of the polymer matrix, the dosage form is retained in the stomach for a prolonged period of time.
In still another aspect, the invention comprises a gastric-retentive, bioerodible active agent dosage form adapted to deliver a therapeutically-effective amount of an active agent selected from the group of antiviral agents, antifungal agents and antibiotic agents at a controlled rate such that the relative absorption index of the active agent delivered is at least 0.5, and preferably greater than 1.
In a further aspect of the invention, the active agent dosage form comprises a unitary compressed dispersion of a solid active agent in a gel-forming, erodible polymer matrix having a first portion that swells in the stomach while maintaining its physical integrity for a prolonged period of time and a second, non-erodible, non-gel-forming portion for promoting retention of the dosage form in the stomach over a prolonged period of time.
In another aspect, the dosage forms of the invention described above may comprise a gastric-emptying delaying agent, i.e., a substance that increases the retention time of the dosage form in the stomach. The gastric-emptying delaying agent may be combined with the composition containing the active agent for local delivery to the environment of use or it may be coated on the dosage form to provide the desired physiological response to delay onset of the IMMC and facilitate retention of the dosage form in the stomach.